Hepatic encephalopathy (HE) is a neuro-cognitive complication of cirrhosis that is divided into the clinically apparent overt HE (OHE), or minimal HE (MHE), which requires cognitive testing. MHE is associated with poor quality of life (QOL), impaired driving skills, and high risk of OHE development. Criteria used to categorize cirrhotics into normal, MHE and OHE are subjective and not reproducible. This subjectivity and lack of correlation with clinically relevant outcomes is a major gap in our knowledge. Since HE is a continuum, a more productive approach may be to quantify it using continuous measures that locate the patient within the spectrum of neuro-cognitive impairment in cirrhosis (SONIC). Such an approach would allow quantitative assessment in cognitive changes following progression of liver disease, as well as improvement in response to liver transplant (LT). Our central hypothesis is: In subjects with cirrhosis, the degree of impairment and the rate of deterioration of neuro-cognitive function, predicts development of (1) overt hepatic encephalopathy (2) hepatic encephalopathy-related medical and psychosocial outcomes and (3) reversibility of neuro-cognitive course after liver transplant. The specific aims include: (1) Develop a model of SONIC to predict the HE-related medical and psycho-social outcomes in cirrhosis. 300 cirrhotics without OHE will undergo testing with a multi-dimensional cognitive battery, driving history, socio- economic status and QOL. These will be repeated every 6 months until the primary endpoint of OHE development. Hospitalization, accidents, QOL and socio-economic status will be secondary endpoints. The hypothesis is that a multi-dimensional cognitive model will provide a sensitive and specific method of quantifying SONIC that will (a) predict OHE and hospitalization development, and (b) quantify impairment in quality of life, driving and socio-economic status. (2) Define the impact of liver transplant on SONIC and to determine patho-physiological factors that modulate reversibility of cognitive dysfunction after liver transplant: 45 patients on the transplant list will undergo SONIC testing prior to, and at six and twelve months post-LT. The impact of pre-LT cognitive dysfunction severity and MR assessment (MR spectroscopy, diffusion-tensor imaging and functional MR) on reversibility of SONIC after LT will also be defined. The hypothesis is that pre-LT cognitive dysfunction severity and its underlying patho-physiology determines the degree of reversibility post-LT. This contribution is significant as it is expected to engender a paradigm shift in the evaluation of cognition in cirrhosis by integrating an objective approach to predict medical and psycho-social outcomes, and by defining the impact of transplant on cognition. Such results will have a positive impact, because it will introduce objectivity into this field and define the patho-physiology as well as cognitive outcome of SONIC after transplant. This would improve diagnostic and therapeutic strategies for cognitive testing in cirrhosis as well as improve patient selection for transplant. PUBLIC HEALTH RELEVANCE: The proposed studies will change the way patients with cirrhosis are approached and will replace the current faulty system of categorizing their brain function with a better method of predicting how the effect of cirrhosis on the brain affect patients' medical outcomes as well as their quality of life and ability to work and earn and how much of these defects change after liver transplant. These procedures will then make it easier for doctors to diagnose, predict complications and treat patients with cirrhosis. Thus, the findings are ultimately expected to be applicable in improving the health of patients with cirrhosis, which is one of the leading causes of death.